Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial
Domenica M Rubino, Frank L Greenway, Usman Khalid, Patrick M O'Neil, Julio Rosenstock, Rasmus Sørrig, Thomas A Wadden, Alicja Wizert, W Timothy Garvey, STEP 8 Investigators, Carlos Arauz-Pacheco, Kevin Cannon, H Jackson Downey, David Fitz-Patrick, Jeffrey Geohas, Gregg Gerety, John Gilbert, Priscilla Hollander, Eric Klein, Karen Laufer, Philip O'Donnell, Paul Rosenblit, Phillip Toth, Domenica M Rubino, Frank L Greenway, Usman Khalid, Patrick M O'Neil, Julio Rosenstock, Rasmus Sørrig, Thomas A Wadden, Alicja Wizert, W Timothy Garvey, STEP 8 Investigators, Carlos Arauz-Pacheco, Kevin Cannon, H Jackson Downey, David Fitz-Patrick, Jeffrey Geohas, Gregg Gerety, John Gilbert, Priscilla Hollander, Eric Klein, Karen Laufer, Philip O'Donnell, Paul Rosenblit, Phillip Toth
Abstract
Importance: Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management.
Objective: To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity.
Design, setting, and participants: Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338).
Interventions: Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85).
Main outcomes and measures: The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points.
Results: Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide.
Conclusions and relevance: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks.
Trial registration: ClinicalTrials.gov Identifier: NCT04074161.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Rubino reported being a clinical investigator for Boehringer Ingelheim, AstraZeneca, and Novo Nordisk; receiving honoraria from WebMD, speaker fees, consulting fees, scientific advisory fees, and honoraria from Novo Nordisk, grants from SARL, and personal fees from Medscape, PeerView, and the Endocrine Society; and being a shareholder in Novo Nordisk. Dr Greenway reported receiving grants from Novo Nordisk, Pennington Biomedical Research Center, and NuSirt to his institution during the conduct of the study and personal fees from Pfizer, NovMeta Pharma, Melior Discoveries, Jenny Craig, Basic Research, Gedeon Richter Pharma, Jazz Pharmaceuticals, General Nutrition Corp, Dr Reddy’s Lab, and Regeneron and stock ownership in Academic Technology Ventures, Energesis, Ketogenic Health Systems, MetaSYn Therapeutics, Plensat, Slim Health Nutrition, UR Labs, and Rejuvenate Bio. In addition, Dr Greenway has a patent issued for orlistat and a patent pending for pramlintide/albuterol. Also, Dr Greenway served on the Novo Nordisk advisory board for the development of liraglutide that is now approved and was a comparator drug in the trial described in the present article. Dr Khalid reported being an employee of Novo Nordisk. Dr O’Neil reported receiving grants from Novo Nordisk during the conduct of the study and grants from WW International, Eli Lilly, and Epitomee Medical and personal fees from Pfizer, Robard Corporation, Novo Nordisk, WebMD, and Gedeon Richter outside the submitted work. Dr Rosenstock reported receiving scientific advisory board fees, honoraria, consulting fees, and grants/research support from Novo Nordisk (during the conduct of the study and outside the submitted work), Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Intarcia, Oramed, Hanmi, and Sanofi; honoraria or consulting fees from Zealand; and grants/research support from Genentech, Novartis, Pfizer, REMD Biotherapeutics, vTv Therapeutics, Metacrine, Merck, and Janssen outside the submitted work. Dr Sørrig reported being a full-time employee and shareholder of Novo Nordisk. Dr Wadden reported receiving grants from Novo Nordisk on behalf of the University of Pennsylvania and scientific advisory board fees from Novo Nordisk and WW (formerly Weight Watchers). Dr Wizert reported being a full-time employee and shareholder of Novo Nordisk. Dr Garvey reported receiving grants from Novo Nordisk; serving as site principal investigator for the clinical trial, which was sponsored by his university during the conduct of the study; receiving grants from Lexicon, Pfizer, Eli Lilly, and Epitomee outside the submitted work; and serving as an ad hoc consultant on advisory committees for Jazz Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, and Pfizer. In each instance, he received no financial compensation, nor was there a financial relationship.
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Source: PubMed